The present invention relates to pharmaceutical combinations useful in the treatment of cancer. Particularly, the combinations of this invention relate to dioxolane nucleosides with at least one further therapeutic agent chosen from nucleoside analogues and/or chemotherapeutic agents.
Cancer is the second leading cause of death in the United States. It is estimated that cancer is responsible for 30% of all deaths in the Western world. Lung, colorectal, breast and prostate cancers are the four biggest killers.
Many nucleoside analogues have been found to possess anticancer activity. It was reported in (Weitman et al Clinical Cancer Research (2000), 6(4), pp 1574-1578 and Giles et al Journal of Clinical Oncology (2001), 19(3), pp 762-771 and also Gourdeau et al Cancer Chemother. Pharmacol. (2001), 47(3), pp 236-240) that troxacitabine (xcex2-L-dioxolane cytidine, xcex2-L-OddC, Troxatyl(trademark)), a nucleoside analogue, has shown to have potent activity in the treatment of various forms of cancers (e.g. solid tumours, adult leukemia and lymphomas).
Other important nucleoside analogues which are also well known in the treatment of cancer are Cytarabine (Ara-C), fludarabine, gemcitabine and cladribine. In the treatment of leukemia, combinations of cytarabine and anthracyclines have been the subject of most intense study. Despite improvements in the outcome of patients with current combination treatment programs, there exists a need to find other combinations of drugs which exhibit potent antitumor activity. In addition, the current therapies fail to cure most cancers once they have recurred.
The present invention provides combinations of troxacitabine with other nucleoside analogues and/or chemotherapeutic agents which exhibit potent antitumor activity and would greatly aid in the development of new combination therapy against cancer.
In one aspect, the present invention provides a novel pharmaceutical combination useful for the treatment of cancer in a mammal comprising at least one active compound of formula (1): 
or a pharmaceutically acceptable salt thereof,
wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl and 
wherein each Rc is independently selected from the group comprising H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and a hydroxy protecting group;
and at least one further therapeutic agent chosen from nucleoside analogue and/or a chemotherapeutic agent.
The pharmaceutical combinations of the present invention are useful in cancer therapy, in particular in the treatment of cancer selected from the group comprising lung cancer, prostate cancer, bladder cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, hepatocellular carcinoma, leukemia and lymphomas in patients.
In another aspect, the pharmaceutical combinations of the present invention are useful in cancer therapy, in particular in the treatment of cancer selected from the group comprising lung cancer, prostate cancer, bladder cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, hepatocellular carcinoma, and lymphomas in patients.
In another aspect, the pharmaceutical combinations of the present invention are useful in cancer therapy, in particular in the treatment of leukemia.
In another aspect, the pharmaceutical combinations of the present invention are useful in cancer therapy, in particular in the treatment of pancreatic cancer.
In another aspect, there is provided a method of treating a patient having cancer comprising administering to said patient a therapeutically effective amount of a compound of formula (I) and at least one further therapeutic agent.
In another aspect, there is provided a method of treating a patient having cancer, in particular in the treatment of cancer selected from the group comprising lung cancer, prostate cancer, bladder cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, hepatocellular carcinoma, leukemia and lymphomas, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) and at least one further therapeutic agent.
In another aspect, there is provided a method of treating a patient having a cancer, in particular a cancer other than leukemia, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) and at least one further therapeutic agent.
In another aspect, there is provided a method of treating a patient having cancer, in particular in the treatment of cancer selected from the group comprising lung cancer, prostate cancer, bladder cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, hepatocellular carcinoma, and lymphomas, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) and at least one further therapeutic agent.
In another aspect, there is provided a method of treating a patient having cancer, in particular in the treatment of refractory leukemia comprising administering to said patient having refractory leukemia a therapeutically effective amount of a compound of formula (I) and at least one further therapeutic agent. Preferably, the further therapeutic agent is other than doxorubicin. Also, the ratio of the compound of formula (I) to the further therapeutic agent is preferably 1:250 to 250:1, more preferably 1:50 to 50:1, especially 1:20 to 20:1.
In another aspect, there is provided a pharmaceutical formulation comprising the combination of the compound of formula (I) and at least one further therapeutic agent in combination with at least a pharmaceutically acceptable carrier or excipient. Preferably, the further therapeutic agent is other than doxorubicin. Also, the ratio of the compound of formula (I) to the further therapeutic agent is preferably 1:250 to 250:1, more preferably 1:50 to 50:1, especially 1:20 to 20:1.
Another aspect of the invention is the use of a compound according to formula (I) and at least one further therapeutic agent, for the manufacture of a medicament for treating cancer in a mammal. Preferably, the further therapeutic agent is other than doxorubicin. Also, the ratio of the compound of formula (I) to the further therapeutic agent is preferably 1:250 to 250:1, more preferably 1:50 to 50:1, especially 1:20 to 20:1.